In-hospital mortality risk stratification in children aged under 5 years with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership to Assess WHO REcommendations (PREPARE) dataset

Highlights • Children with pneumonia whose oxygen level was measured had a lower risk of death.• Hypoxemia was frequent among danger signs and chest-indrawing pneumonia cases.• Pulse oximeters are essential tools for hospital-based child pneumonia care.• Additional interventions to reduce in-hospital pneumonia deaths should be explored.


Background
Pneumonia and other acute lower respiratory infections (ALRIs) remain the leading cause of death in children aged 1-59 months [1] . Over the last 2 decades, substantial progress has been made to reduce mortality and limit unnecessary hospitalizations. Randomized controlled trials demonstrated that children aged 2-59 months with chest-indrawing pneumonia without any general danger sign experience similar treatment failure rates with oral amoxicillin as those managed with injectable penicillin [2][3][4] . In response to these findings, in 2012 the World Health Organization (WHO) revised their pneumonia management guideline [5] , which was included in the second edition of the WHO Pocket book of hospital care for children [6] and the Integrated Management of Childhood Illness chart booklet [7] in 2014 ( Box 1 ) [6 , 8] . It recommends that children aged 2-59 months without HIV with chest indrawing but without general danger signs (unable to drink/feed; convulsions; sleepy/lethargic; vomiting everything; severe wheezing; and signs of respiratory distress, including grunting, head nodding, nasal flaring), stridor, severe malnutrition, or hypoxemia (defined as a peripheral transcutaneous oxyhemoglobin saturation [SpO 2 ] < 90%) can be treated with oral amoxicillin. Other trials in India [9] , Malawi [10] , Kenya [11] , and Pakistan [12 , 13] and two observational studies in Papua New Guinea [14] and Kenya [15] demonstrated that these children could be safely treated with oral antibiotics at home. However, most studies screened for and excluded hypoxemic children, using definitions ranging from SpO 2 < 90% to < 85%. In addition, none were powered to demonstrate the differences in mortality [4] . Not applicable a Fast breathing for age: RR ≥50 bpm in those aged 2-11 months and RR ≥40 bpm in those aged 12-59 month; b Danger signs are either according to WHO pocketbook (i.e., central cyanosis, apnea, gasping, grunting, nasal flaring, severe wheezing, head nodding) or according to IMCI general danger sign (inability to drink, lethargy or unconscious, convulsions, vomit everything), stridor in a calm child or weight-for-age z-score < -3. bpm, breaths per minute; RR, respiration rate WHO, World Health Organization.
Chest indrawing is a cardinal feature of respiratory distress that precedes hypoxemia and respiratory failure in children. This inward movement of abdominal and chest wall soft tissue below the rib cage is due to the increased negative intrapleural pressures generated to expand lungs with poor compliance during inspiration [16] . Hypoxemia occurs most commonly when there is ventilation perfusion mismatch in the lungs from an ALRI and is most frequently measured noninvasively by a pulse oximeter device [17] . However, before COVID-19, when the data for the current analysis were collected, pulse oximetry was limited in many low-resource settings, particularly in primary and community care [18 , 19] . It is recognized that in the absence of pulse oximetry, the WHO Integrated Management of Childhood Illness protocol may miss hypoxemia, leading to misclassification of patients who need oxygen and inpatient care [20][21][22][23][24][25] . A retrospective Kenyan study conducted in district hospitals without pulse oximeters found that, apart from danger signs, mild to moderate pallor, age < 12 months, lower chest indrawing, respiratory rate of 70 breaths or more, admission to a hospital in a malaria-endemic region, and moderate malnutrition were independently associated with pneumonia-related mortality [26] .
The overall goal of this study was to understand the value of pulse oximetry in evaluating hospitalized children with pneumonia. We also explored additional clinical characteristics that were risk factors for chest-indrawing pneumonia mortality and could therefore be used to identify children with a high mortality risk. Using the WHO Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) study dataset, we aimed to (i) describe and compare the clinical characteristics and case fatality risk (CFR) by pneumonia severity among children with and without a pulse oximetry reading at study enrollment and (ii) determine inhospital mortality risk factors among children aged 2-59 months with chest-indrawing pneumonia, with and without pulse oximetry measurements.

Study sample
We conducted a secondary analysis of collated datasets from 41 studies included in the WHO PREPARE project. These studies were conducted in 31 countries, including 29 low-middle-income countries (LMICs). Figure 1 describes how the analytic dataset was selected and used for this analysis. A detailed description of the studies is shown in Table 1 [2 , 3 , 27-48] . The primary data collection occurred between 1994 and 2014, and countries were at varying stages of Pneumococcus and Haemophilus influenzae type B (Hib) vaccine implementation.

Inclusion and exclusion criteria
The patient records of hospitalized children aged 2-59 months with WHO-defined pneumonia and had survival outcome were included in the current analyses. We excluded patient records from community-based studies, those without WHO signs for pneumonia classification, or those who had no survival outcomes ( Figure 1 ). Children received hospital-based care, including antibiotics and supplemental oxygen when indicated and available according to local norms.

Definitions and variables
The WHO pneumonia severity was defined as fast breathing (respiratory rate above the age-specific cut-off), chest indrawing, or danger sign ( Box 1 ). Before the 2012 WHO guidance revision [5] , it was recommended that all children with chest indrawing, even those without danger signs, should be hospitalized for injectable antibiotics and supportive care. Variables were chosen a priori due to clinical significance and potential association with mortality based on previous studies. These variables include: age, sex, weight, weight-for-age z-score, temperature (normothermia [35.5-37.9 °C], fever [ ≥38 °C], and hypothermia [ < 35.5 °C]), ageadjusted tachypnea, severe tachypnea (defined as respiratory rate ≥70 breaths per minute), signs of severe respiratory distress ( i.e ., grunting, head nodding, or nasal flaring), and SpO 2 (if reported) [6 , 7 , 20] . Although pallor and residence in malaria hyperendemic regions have been previously described as pneumonia-related mortality risk factors [26] , these data were not routinely included in our dataset. Some of the studies that contributed to the dataset were multicountry and included malaria hyperendemic regions and nonhyperendemic regions, but the dataset identifies cases by study and does not include if the case was from a specific country. Our primary outcome of interest was in-hospital pneumoniarelated mortality.

Statistical analysis
To address the first objective, we described and compared the frequency, proportion with 95% confidence interval (CI), mean, median, and missingness of data on the clinical characteristics at the time of admission by pneumonia severity and if pulse oximetry was measured. Then, we reported the CFR by WHO pneumonia severity and compared these CFRs by the presence of pulse oximetry measurements. Pulse oximetry was categorized into no SpO 2 measurement and any SpO 2 measured at presentation. The measured group was further stratified into SpO 2 < 90%, 90-92%, and 93-100% to explore the impact of these categories on CFR [49 , 50] .
For the second objective, we exclusively used the data from the chest-indrawing pneumonia cases subset to fit two mixedeffects logistic regression models to explore the associations between demographic characteristics, nutritional status, and clinical signs at initial presentation with mortality. Mixed-effects modeling was chosen because some parameters had clear fixed effects on the outcome (tachypnea vs no tachypnea), whereas we assumed other parameters had a variable or unknown effect on the outcome (male vs female). In addition, we included variables to reflect the study type (observational vs randomized controlled trial) and pneumococcal vaccine (PCV) implementation at time of data collection because these factors had clear effects on mortality. Heterogeneity was accounted for at each study level. The first model included chest-indrawing cases with pulse oximetry measurements at hospitalization, and the second included those without pulse oximetry measurements. In the model that included pulse oximetry, SpO 2 categories ( < 90%, 90-92%, and > 93%) were treated as ordinal co-variables. To assess for bias, we described the variable missingness. We then conducted a bivariate analysis with complete cases. Variables with > 15% missingness were excluded from the multivariable model. We reported the adjusted odds ratio (aOR) with 95% CI.

Included studies
Among the 285,839 children from 41 studies in the PREPARE dataset, 164,244 (57.5%) from 26 of the 41 included studies (conducted in 29 countries) met the inclusion criteria for analysis ( Figure 1 and Table 1 ). All cases that met the inclusion criteria were enrolled in-hospital-based studies. Pulse oximetry measurements were reported in 27.8% (n = 45,675) of cases. Among the 164,244 children included in the analyses, there were 7921 deaths (CFR 4.8%). Of included cases, 12.6% (n = 20,672) had only fastbreathing pneumonia, 39.1% (n = 64,256) had chest indrawing with or without fast breathing, and 48.3% (n = 79,316) had any danger sign at the time of admission.

Clinical characteristics
The overall hypoxemia (SpO 2 < 90%) prevalence was 17.7% (95% CI 17.3-18.0%). A nearly similar prevalence of hypoxemia was observed in patients with chest-indrawing pneumonia (19.7%; 95% CI 19.0-20.4%) and patients with danger sign pneumonia (20.7%; 95% CI 20.2-21.2%). Of the 164,244 cases in the dataset, 6.1% reported data on signs of severe respiratory distress. Children with chest-indrawing pneumonia with and without pulse oximetry measurements had similar characteristics except for differences in the prevalence of temperature ≥38 °C (35.9% with vs 40.5% without SpO 2 ) and severe tachypnea (10.7% with vs 13.9% without SpO 2 ), which might reflect the differences in frequency of missing data among cases without an SpO 2 measurement ( Table 2 ). Among fast-breathing pneumonia cases, a larger proportion of children with versus without pulse oximetry measurements were aged 2-5 months (14.1% with vs 9.7% without SpO 2 ). Otherwise, the demographic and clinical characteristics by pneumonia severity were similar between the SpO 2 measured and not measured cohorts.

Case fatality risk
In Table 3 , we compare the CFR of cases with and without pulse oximetry integrated into their care. Column 1 reflects the data from four studies with 100% missing SpO 2 values. Pulse oximetry was not documented in these studies because it was not integrated into the overall study design. Column 2 reflects the data from studies with < 100% missing values. Except for two retrospective studies by Lu (55.5%) and Wulandari (26.0%), all studies had < 15% missing SpO 2 values. We chose to include the Lu and Wulandari studies in column 2 because the subanalyses suggested that pulse oximetry measurements were missing at random because there was no difference in the CFR among children with and without a documented SpO 2 measurement. Most missing measurements were in children with fast-breathing pneumonia, and pulse oximetry is routinely not used in these cases.

Discussion
In this study, the CFR of cases with an SpO 2 measurement was lower than those without. Hypoxemia of SpO 2 < 90% was highly prevalent among children with chest-indrawing or danger sign pneumonia. Patients with chest-indrawing and danger sign pneumonia with an SpO 2 < 90% had a CFR of 10.3% and 11.8%, respectively. Age bands 2-5 months and 6-11 months, SpO 2 < 90%, moderate malnutrition, and female sex were independently associated with chest-indrawing pneumonia-related in-hospital death. We used a large multicountry dataset of hospitalized patients with pneumonia to explore the clinical outcomes in child pneumonia cases with and without SpO 2 measurement and focused on cases with chest-indrawing pneumonia. Given the size of the dataset, our post hoc power estimate was greater than 95%. All data-contributing studies were conducted before the implementation of the 2012 WHO pneumonia management guidance recommending that children with chest-indrawing pneumonia without danger signs or hypoxemia (if pulse oximetry is available) could be safely managed in outpatient settings with oral amoxicillin [5] .
The CFR was higher among child pneumonia cases without a documented SpO 2 measurement. The reduced CFR with pulse oximeter use may reflect the impact of pulse oximetry on hospital outcomes or effects of a more functional health system [51] . Healthcare worker identification of hypoxemia likely influenced if a child received supplemental oxygen [52 , 53] . In contrast, clinicians may use pulse oximetry as an objective measurement to improve their assessments, which, in some cases, may result in the de-escalation of unnecessary care, presumably freeing up resources for children who could benefit from them [54] . Pulse oximetry implementation has been shown to increase the diagnosis of pneumonia [55] , improve the overall quality of care for pneumonia and malaria [19 , 56] , and decrease hospital-based pediatric ALRI mortality, independent of supplemental oxygen availability [57] .
Our hypoxemia prevalence and some of our CFR findings differ from other published reports. Our estimates are slightly higher than that of a 2009 metanalysis [58] . This study included a small amount of data ( < 10%) from studies that enrolled children aged up to 12 years. Hypoxemic pneumonia is less frequent in older children, which may explain their slightly lower estimates. In contrast, our findings are much lower than that reported by two meta-analyses [59 , 60] and the Pneumonia Etiology Research for Child Health (PERCH) study [61] (47-35.8%). Misclassification bias could explain these differences. In the PERCH study, at most study sites, hypoxemia was defined as an SpO 2 < 92%. In Rahman et al. 's metanalysis, they were unable to disaggregate data, and 17 of the 57 included studies defined hypoxemia as an SpO 2 < 92-95% [60] . All four studies presented combined chest-indrawing and danger sign cases into one cohort when describing hypoxemia frequency. In previous works [49 , 50 , 62] conducted in countries with a high anemia prevalence [63] , an SpO 2 of 90-92% was proposed as an ALRI-associated mortality risk factor, independent of clinical severity, but this was not associated with chestindrawing pneumonia mortality in our data. In our study, hypoxemia (SpO 2 < 90%) prevalence was high and it put children, particularly those with chest indrawing or danger signs, at risk for death. Despite the WHO's recommendation to use pulse oximetry to assess hypoxemia and clear evidence that pulse oximeters are essential medical devices, many outpatient facilities and hospitals in LMICs do not have or do not use pulse oximeters in routine care [18 , 19 , 64-67] . Unfortunately, clinical signs alone are not reliable predictors of hypoxemia, resulting in both falsepositive and false-negative classifications, leading to many hypoxemic children not receiving oxygen and potentially contributing to pneumonia-related deaths [20 , 53 , 68] . Global uptake of pulse oximeters at the health system level will take time due to funding and implementation challenges, such as procurement, training, promotion of use, and ongoing monitoring and feedback [19 , 69] . Nonetheless, pulse oximetry implementation is a necessary investment. The value of pulse oximetry is clear; however, other factors may play an important role in reducing chest-indrawing pneumonia deaths. Unlike children with chest-indrawing pneumonia receiving outpatient care, the children in this study had access to supplemental oxygen and hospital-based care and received injectable antibiotics yet they still died. Similar to ours, other studies identified age 2-11 months, moderate malnutrition, severe tachypnoea, and female sex as mortality risk factors among children with pneumonia [26 , 49 , 70] . These risk factors are plausible. Sexbased health disparities, including delayed care seeking, have been demonstrated in Africa and Asia and may explain some of these findings [26 , 49 , 71-73] . The excess mortality burden in infancy may reflect incomplete vaccination or a higher risk of occult untreated serious bacterial infection other than pneumonia, such as bacteremia, urinary tract infection, malaria, and meningitis [74 , 75] . Exploratory studies are necessary to identify how these risk factors could inform medical decision making in the triage, followup, and hospital care of children with chest-indrawing pneumonia. Although known to contribute to pneumonia-related [76] and allcause mortality, there is no formal disease-specific guidance on the care of children who are moderately malnourished. Targeted interventions could reduce pneumonia-related mortality in this group. For instance, the association of enteral protein intake during hospitalization with reduced 60-day mortality is well documented in critically ill children who are mechanically ventilated, independent of baseline nutrition status [77] . It is plausible that protein supplementation could reduce pneumonia-related mortality, particularly in children who are moderately malnourished. An ongoing phase II randomized controlled trial in Kenya and Uganda addresses this issue in children with severe (danger sign) pneumonia [78] . Other potential studies could evaluate if close outpatient follow-up, earlier hospital referral, or more intensive in-hospital monitoring of select groups, such as young infants aged 2-5 months, may reduce hospitalized pneumonia deaths.

Limitations
This study had some limitations. First, most of these data are derived from studies conducted before or during the widespread PCV and Hib vaccine implementation. Accordingly, we may be overestimating the prevalence of severe and hypoxemic pneumonia and its associated mortality because 73% of infants now receive Hib vaccine, and around 45% receive PCV [79] . However, suggesting otherwise, our findings have a similar CFR as that of the PERCH study (6.7%), which examined the etiology of severe pneumonia in the postpneumococcal vaccination era [61] . Second, because the studies included in our dataset occurred before the WHO recommendation that chest-indrawing cases be managed with oral amoxicillin, the majority of these cases received injectable antibiotics. Third, HIV co-morbidity data were not commonly documented in the dataset. Pneumonia-associated hypoxemia and mortality are higher among children who are HIV-positive or -exposed [80] . Therefore, our findings are not generalizable to this highrisk patient group. In addition, other co-infections, such as malaria, were not accounted for [74] . Although, this may also reflect realworld conditions in settings without reliable HIV and malaria testing resources. Fourth, there are inherent differences in pulse oximeter devices, training, and supervision, which could affect the accuracy of SpO 2 measurements and our findings. Fifth, only 6.1% of this dataset included information on signs of respiratory distress. Given that these are considered danger signs that warrant hospitalization, we cannot be certain that some of the cases with chest indrawing did not also have signs of respiratory distress. Sixth, we collated data from a diverse range of settings and a large proportion of unmeasured pulse oximetry cases came from a single 10-year study in Malawi. To address this, we conducted a sen- sitivity analysis and found that moderate malnutrition remained a mortality risk factor even when the Malawian cases were excluded. Seventh, we were unable to assess for study-level variance in the duration of illness before hospitalization, length of hospitalization, and time to inpatient death, which may reflect the differences in care-seeking behaviors and clinician judgment to hospitalize a patient. There are certainly other unmeasured factors affecting child pneumonia in-hospital mortality, which we are unable to account for. Finally, we aggregated data from a wide variety of studies conducted in many different countries, which may limit the applicability of our findings to local contexts. Some of the data are from clinical trials or prospective studies with dedicated study staff, whereas others are from routine care settings; as such, there is variability in the quality of the reported data. We are unable to account for how management differences affected the patient outcomes. From an implementation perspective, the use of data collected outside of a funded, well-staffed, and well-supplied clinical trial may be a strength because these data more accurately reflect the real-world conditions of healthcare delivery in LMICs.

Conclusion
Pulse oximetry use is critical to providing effective pneumonia care. Given that many LMIC ALRI care settings do not have or use pulse oximeters and that danger signs and chest-indrawing cases had a high prevalence of hypoxemia and associated CFR, we can conclude that many children who could benefit from supplemental oxygen are going unrecognized. This represents a missed opportunity to reduce child pneumonia deaths. A substantial proportion of chest-indrawing pneumonia deaths were not hypoxemic.
Exploratory research is needed to understand how mortality risk factors, such as moderate malnutrition and young age, could be used to guide care to reduce mortality. Our findings suggest that pulse oximetry should be integrated in the clinical evaluation of children aged 5 years who are hospitalized with ALRI, particularly for children with chest-indrawing pneumonia.

Declaration of competing interest
The authors have no competing interests to declare. YBN is a staff member of the WHO. The expressed views and opinions do not necessarily represent the policies of the WHO.

Ethical approval
All studies included in this deidentified data set were previously granted clearance by ethical review boards at each participating site.

Author contributions
SAQ secured the funding. SH, CKin, YBN, and SAQ conceptualized and designed the study, interpreted the data, and wrote the first draft of the manuscript. YBN verified the data and conducted statistical analyses . CKin, EDM, TC, NL, CM, CG, ST, CC, SM, MN,  BG, TH, JM, EA, NC, MH, PH, PJ, JL, WM, AP, DT, NN, SZ, RR, ML,  CK, CT, RA, SB, II, IM, GM, SKS, MS, SS, SAwa, AB, MC, PN, JP, VR, GR, MSyl, PV, JW, SBha, TS, MN, LA, ME, SBas, NW, RL, SA, AG, MC, SHir, KO, AC, CR, HC, HN, JF, LW, and MH oversaw the data collection, verified the data, assisted with interpretation of the data, and reviewed and edited the final manuscript. SH and YBN had final responsibility for the decision to submit for publication.

Data sharing
Data used for this study will be available upon request. Deidentified participant data and a data dictionary will be made available after all planned analyses are completed. Data will be shared after approval of request. All data requests should be directed to the corresponding author, Dr. Yasir Bin Nisar.

Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.ijid.2023.02.005 .